Reactive oxygen species in vascular biology: role in arterial hypertension

The cellular metabolism of oxygen generates potentially deleterious reactive oxygen species, including superoxide anion, hydrogen peroxide and hydroxyl radical. Under normal physiologic conditions, the rate and magnitude of oxidant formation is balanced by the rate of oxidant elimination. However, an imbalance between pro-oxidants and antioxidants results in oxidative stress, which is the pathogenic outcome of the overproduction of oxidants that overwhelms the cellular antioxidant capacity. There is growing evidence that increased oxidative stress and associated oxidative damage are mediators of vascular injury in cardiovascular pathologies, including hypertension, atherosclerosis and ischemia–reperfusion. This development has evoked considerable interest because of the possibilities that therapies targeted against reactive oxygen intermediates by decreasing the generation of reactive oxygen species and/or by increasing availability of antioxidants may be useful in minimizing vascular injury. This review focuses on the vascular actions of reactive oxygen species, the role of oxidative stress in vascular damage in hypertension and the therapeutic potential of modulating oxygen radical bioavailability in hypertension. In particular, the following topics will be highlighted: chemistry and sources of reactive oxygen species, antioxidant defense mechanisms, signaling events mediated by reactive oxygen species, role of reactive oxygen species in hypertension and the putative therapeutic role of antioxidants in cardiovascular disease.     

Systems biology of antioxidants

Understanding the role of oxidative injury will allow for therapy with agents that scavenge ROS (reactive oxygen species) and antioxidants in the management of several diseases related to free radical damage. The majority of free radicals are generated by mitochondria as a consequence of the mitochondrial cycle, whereas free radical accumulation is limited by the action of a variety of antioxidant processes that reside in every cell. In the present review, we provide an overview of the mitochondrial generation of ROS and discuss the role of ROS in the regulation of endothelial and adipocyte function. Moreover, we also discuss recent findings on the role of ROS in sepsis, cerebral ataxia and stroke. These results provide avenues for the therapeutic potential of antioxidants in a variety of diseases.     

Peroxiredoxin 6 Fails to Limit Phospholipid Peroxidation in Lung from Cftr-Knockout Mice Subjected to Oxidative Challenge

Oxidative stress plays a prominent role in the pathophysiology of cystic fibrosis (CF). Despite the presence of oxidative stress markers and a decreased antioxidant capacity in CF airway lining fluid, few studies have focused on the oxidant/antioxidant balance in CF cells. The aim of the current study was to investigate the cellular levels of reactive oxygen species (ROS), oxidative damage and enzymatic antioxidant defenses in the lung of Cftr-knockout mice in basal conditions and as a response to oxidative insult.     

NADPH oxidases, reactive oxygen species, and hypertension: clinical implications and therapeutic possibilities

Reactive oxygen species (ROS) influence many physiological processes including host defense, hormone biosynthesis, fertilization, and cellular signaling. Increased ROS production (termed "oxidative stress") has been implicated in various pathologies, including hypertension, atherosclerosis, diabetes, and chronic kidney disease. A major source for vascular and renal ROS is a family of nonphagocytic NAD(P)H oxidases, including the prototypic Nox2 homolog-based NAD(P)H oxidase, as well as other NAD(P)H oxidases, such as Nox1 and Nox4. Other possible sources include mitochondrial electron transport enzymes, xanthine oxidase, cyclooxygenase, lipoxygenase, and uncoupled nitric oxide synthase. NAD(P)H oxidase-derived ROS plays a physiological role in the regulation of endothelial function and vascular tone and a pathophysiological role in endothelial dysfunction, inflammation, hypertrophy, apoptosis, migration, fibrosis, angiogenesis, and rarefaction, important processes underlying cardiovascular and renal remodeling in hypertension and diabetes. These findings have evoked considerable interest because of the possibilities that therapies against nonphagocytic NAD(P)H oxidase to decrease ROS generation and/or strategies to increase nitric oxide (NO) availability and antioxidants may be useful in minimizing vascular injury and renal dysfunction and thereby prevent or regress target organ damage associated with hypertension and diabetes. Here we highlight current developments in the field of reactive oxygen species and cardiovascular disease, focusing specifically on the recently identified novel Nox family of NAD(P)H oxidases in hypertension. We also discuss the potential role of targeting ROS as a therapeutic possibility in the management of hypertension and cardiovascular disease.     

Oxidative stress and mild hypertension

Reactive oxygen species (ROS) play a crucial role in development of hypertension. An increase in production of superoxide anion and hydrogen peroxide, reduction of nitric oxide synthesis, and a decrease in bioavailability of antioxidants have been demonstrated in human hypertension. Oxidative stress resulted in vascular injury, renal dysfunction, and hypertensive end-organ damage. However, recent clinical trials failed to show cardiovascular benefits of antioxidants. Furthermore, none of the large clinical trials were designed to demonstrate effects of specific antioxidants on blood pressure and development of mild hypertension. Research of ROS, oxidative stress, redox signaling, and hypertension is more important than ever. The role of oxidative stress in the development of mild hypertension will need to be undertaken.     

脓毒症氧化应激与抗氧化治疗研究进展

脓毒症(sepsis)是感染引起的全身炎性反应综合征,是急危重患者的严重并发症之一。氧化应激是机体活性氧簇和活性氮簇产生过多或清除能力下降,导致潜在性损伤的病理过程。氧化应激在脓毒症发生、发展中发挥重要作用,早期进行抗氧化干预可能有益于脓毒症防治。丙酮酸乙酯(ethyl pyruvate,EP)是一种稳定的丙酮酸酯类衍生物,它对于发生急性损伤的器官具有显著的保护作用。本文就脓毒症氧化应激与丙酮酸乙酯抗氧化治疗的最新进展作一综述。     

Oxidative stress induced in pathologies: the role of antioxidants.

Exposure to oxidant molecules issued from the environment (pollution, radiation), nutrition, or pathologies can generate reactive oxygen species (ROS for example, H2O2, O2-, OH). These free radicals can alter DNA, proteins and/or membrane phospholipids. Depletion of intracellular antioxidants in acute oxidative stress or in various diseases increases intracellular ROS accumulation. This in turn is responsible for several chronic pathologies including cancer, neurodegenerative or cardiovascular pathologies. Thus, to prevent against cellular damages associated with oxidative stress it is important to balance the ratio of antioxidants to oxidants by supplementation or by cell induction of antioxidants.     

Oxidative stress as a novel target in pediatric sepsis management

Sepsis with secondary multisystem organ dysfunction syndrome is the leading cause of death in the pediatric intensive care unit. Increased reactive oxygen species may influence circulating and endothelial cells, contributing to inflammatory tissue injury and explaining the tissue hypoxia paradigm based on microvascular dysfunction. An impaired mitochondrial cellular oxygen utilization, rather than inadequate oxygen delivery, was claimed to play a more important role in the development of multisystem organ dysfunction syndrome. Anyway, it seems plausible that reactive oxygen species can mediate the pathophysiologic processes occurring in sepsis. However, the consensus guidelines for the management of patients with these conditions do not include the enhancement of antioxidant potential. Therefore, further investigation is needed to support interventions aimed to attenuate the severity of the systemic compromise by abrogating the mechanism of oxidative damage. Antioxidant supplementation currently in use lacks a mechanistic support. Specific pharmacologic targets, such as mitochondria or Nicotinamide Adenine Dinucleotide Phospate-Oxidase (NADPH) oxidase system, need to be explored. Furthermore, the early recognition of oxidative damage in these seriously ill patients and the usefulness of oxidative stress biomarkers to define a cut point for more successful therapeutic antioxidant interventions to be instituted would offer a new strategy to improve the outcome of critically ill children.     

Role of oxidative stress in heart failure

Recent experimental and clinical studies have suggested that oxidative stress is enhanced in heart failure. The production of oxygen radicals is increased in the failing heart whereas antioxidant enzyme activities are preserved normal. Mitochondrial electron transport is an enzymatic source of oxygen radical generation and also a target against oxidant-induced damage. Chronic increases in oxygen radical production in the mitochondria can lead to a catastrophic cycle of mitochondrial DNA damage as well as functional decline, further radical generation, and cellular injury. These cellular events might play an important role in the development and progression of myocardial remodeling and failure.     

How does endothelin induce vascular oxidative stress in mineralocorticoid hypertension?

Endothelin and reactive oxygen species have been identified as important mediators in the pathogenesis of hypertension and associated end-organ damage. In the present issue of Clinical Science, Callera and co-workers have provided new evidence that endothelin stimulates mitochondria to generate reactive oxygen species in the vascular wall during mineralocorticoid-induced hypertension in the rat. These studies open a new line of investigation that could be important for the development of therapeutic strategies; however, there still remains a great deal of uncertainty about the mechanisms that define the relationship between endothelin and oxidative stress in hypertension.     

Oxidative stress, reactive oxygen species

Hypertension is a risk factor for cardiovascular and cerebrovascular outcome. Hypertension is associated with oxidative stress. Alteration in endothelial function is an initial step in the pathogenesis of atherosclerosis. A balance between ambient levels of super oxide and released nitric oxide(NO) plays an important role in the maintenance of endothelial function. It is well known that reactive oxygen species, including hydroxy radicals, directly scavenge NO and produce toxic peroxynitrite. Angiotensin II and mechanical stress generate the reactive oxygen species through the activation of NADH/NADPH oxidase in hypertension. Several investigators have shown that oxidative stress is involved in enhanced vascular growth, vascular inflammation, and impaired endothelium-dependent in hypertension. In this review, we would like to explain the role of oxidative stress in hypertensive organ damages.     

Advanced oxidation protein products play critical roles in liver diseases

There is a complex oxidant and antioxidant system that maintains the redox homoeostasis in the liver. While suffering from exogenous or endogenous risk factors, the balance between oxidants and antioxidants is disturbed and excessive reactive oxygen species are generated, resulting in oxidative stress. Oxidative stress is prevalent in various liver diseases and is thought to be involved in their pathophysiology. Advanced oxidation protein products are generated under conditions of oxidative damage and are newly described protein markers of oxidative stress. Previous studies have underscored the universal pathogenic roles of oxidation protein products in various diseases. However, investigations into how these products participate in the development of liver diseases have been superficial and insufficient. In this review, we highlight the current understanding of the roles of advanced oxidation protein products in liver disease pathogenesis and the underlying mechanisms. Moreover, we summarize the current studies on advanced oxidation protein products in infectious and noninfectious, acute and chronic liver diseases. Different strategies for targeting these advanced oxidation protein products and future perspectives, which may pave the way for developing new therapeutic strategies, will also be discussed here.     

Does increased oxidative stress cause hypertension?

Hypertension is associated with increased vascular oxidative stress; however, there is still a debate whether oxidative stress is a cause or a result of hypertension. Animal studies have generally supported the hypothesis that increased blood pressure is associated with increased oxidative stress; however, human studies have been inconsistent. Oxidative stress promotes vascular smooth muscle cell proliferation and hypertrophy and collagen deposition, leading to thickening of the vascular media and narrowing of the vascular lumen. In addition, increased oxidative stress may damage the endothelium and impair endothelium-dependent vascular relaxation and increases vascular contractile activity. All these effects on the vasculature may explain how increased oxidative stress can cause hypertension. Treatment with antioxidants has been suggested to lower oxidative stress and therefore blood pressure. However, to date, clinical studies investigating antioxidant supplements have failed to show any consistent benefit. It is noteworthy that lowering blood pressure with antihypertensive medications is associated with reduced oxidative stress. Therefore, it seems that oxygen stress is not the cause, but rather a consequence, of hypertension.     

Free radical metabolism in human erythrocytes

As the red cell emerges from the bone marrow, it loses its nucleus, ribosomes, and mitochondria and therefore all capacity for protein synthesis. However, because of the high O₂ tension in arterial blood and heme Fe content, reactive oxygen species (ROS) are continuously produced within red cells. Erythrocytes transport large amount of oxygen over their lifespan resulting in oxidative stress. Various factors can lead to the generation of oxidizing radicals such as O₂^•−, H₂O₂, HO^• in erythrocytes. Evidence indicates that many physiological and pathological conditions such as aging, inflammation, eryptosis develop through ROS action. As such, red cells have potent antioxidant protection consisting of enzymatic and nonenzymatic pathways that modify highly ROS into substantially less reactive intermediates.

The object of this review is to shed light on the role of ROS both at physiological and pathological levels and the structural requirements of antioxidants for appreciable radical-scavenging activity. Obviously, much is still to be discovered before we clearly understand mechanisms of free radical systems in erythrocytes. Ongoing trends in the field are recognition of undetermined oxidant/antioxidant interactions and elucidation of important signaling networks in radical metabolism.     

Oxygen: How Do We Stand It?

The electronic structure of ground state oxygen, which is essential for the life of all aerobic organisms, makes it potentially dangerous for those organisms. Atmospheric oxygen contains two unpaired electrons with parallel spin states, which predisposes it to reduction by a univalent pathway. As a consequence, normal aerobic metabolism generates dangerous reactive intermediates of the reduction of O₂. These include superoxide radical (O₂^–), hydrogen peroxide (H₂O₂), and hydroxyl radical (HO). These reactive oxygen species and others that they can engender can damage all cellular macromolecules and unless opposed by cellular defenses, would make aerobic life impossible. Such defenses include superoxide dismutases, catalases, and peroxidases, enzymes that decrease the concentration of the reactive oxygen species that are their substrates, and others that repair or recycle oxidatively damaged macromolecules. Any factor that stimulates reactive oxygen species production or suppresses the antioxidant systems would inevitably cause cell damage. The role of such oxidative damage in various diseases is well documented. In vivo detection of O^2– and other reactive oxygen species is however hampered by the lack of easy, specific, and sensitive analytical methods. Potential artifacts and limitations of the most common detection methods currently in use are briefly discussed.Key Words: Reactive oxygen species, Superoxide, Singlet oxygen, Hydrogen peroxide, Nitric oxide, Free radical, Oxidative stress, Superoxide dismutase, Superoxide assay     

Effects of Hypericum perforatum extract in a rat model of ischemia and reperfusion injury

Oxidative stress results from an oxidant/antioxidant imbalance, an excess of oxidants, and/or a depletion of antioxidants. A considerable body of recent evidence suggests that oxidative stress and exaggerated production of reactive oxygen species play a major role in several aspects ischemia and reperfusion. Hypericum perforatum is a medicinal plant species containing many polyphenolic compounds, namely flavonoids and phenolic acids. Because polyphenolic compounds have high antioxidant potential, in this study we evaluated the effect of H. perforatum extract on splanchnic artery occlusion (SAO) shock-mediated injury. SAO shock was induced in rats by clamping the superior mesenteric artery and the celiac trunk for 45 min. After 1 h of reperfusion, SAO-shocked rats developed a significant fall in mean arterial blood pressure. Treatment of rats with H. perforatum extract (applied at 25 mg/kg 15 min before reperfusion) significantly reduced a significant fall in mean arterial blood pressure and the migration of polymorphonuclear cells caused by SAO-shock. H. perforatum extract also attenuated the ileum injury (histology) as well as the increase in the tissue levels of myeloperoxidase and malondialdehyde caused by SAO shock in the ileum. Immunohistochemical analysis for nitrotyrosine and for poly ADP-ribosylated proteins revealed a positive staining in ileum from SAO-shocked rats. The degree of staining for nitrotyrosine and poly ADP-ribosylated proteins was markedly reduced in tissue sections obtained from SAO-shocked rats that had received H. perforatum extract. Reperfused ileum tissue sections from SAO-shocked rats showed positive staining for P-selectin and for intercellular adhesion molecule-1 in the vascular endothelial cells. H. perforatum extract treatment markedly reduced the intensity and degree of P-selectin and intercellular adhesion molecule-1 in tissue section from SAO-shocked rats. H. perforatum extract treatment significantly improved survival. In conclusion, this study demonstrates that H. perforatum extract exerts multiple protective effects in splanchnic artery occlusion-reperfusion shock and suggests that H. perforatum extract may be a candidate for consideration as a therapeutic intervention for ischemia-reperfusion injury.     

Increased levels of 8-hydroxydeoxyguanosine and its relationship with lipid peroxidation and antioxidant vitamins in lung cancer.

BACKGROUND: Reactive oxygen species produced either endogenously or exogenously can attack lipids, proteins and DNA in human cells and cause potentially deleterious consequences. In recent years, their role in the pathogenesis of lung cancer and the preventive effect of antioxidants have been studied extensively. In this study, our aim was to investigate the levels of 8-hydroxy-2'-deoxyguanosine (8OHdG) and malondialdehyde as a marker for the effects of reactive oxygen species on DNA and lipids, the levels of antioxidant vitamins and the correlations between these oxidative stress markers and antioxidants in lung cancer. METHODS: Serum malondialdehyde, beta-carotene, retinol, and vitamins C and E were measured by high-performance liquid chromatography methods in fasting blood samples and 8OHdG was measured by gas chromatography-mass spectrometry in 24-h urine samples of patients with lung cancer (n=39) and healthy controls (n=31). RESULTS: The levels of 8OHdG and malondialdehyde were significantly higher (p<0.05 and p<0.005, respectively) and beta-carotene, retinol, and vitamins C and E (p<0.0001, p<0.0001, p<0.0001, and p<0.05, respectively) were significantly lower in patients than in controls. There was a significantly positive correlation between 8OHdG and malondialdehyde (r=0.463, p=0.01) and a negative correlation between the levels of 8OHdG and retinol (r=-0.419, p=0.021) in the patient group. CONCLUSIONS: Our results demonstrate that the oxidant/antioxidant balance was spoiled in favor of lipid peroxidation and DNA damage in lung cancer patients. Significant increases in the levels of malondialdehyde and 8OHdG and decreases in the levels of antioxidants suggest the possible involvement of oxidative stress in lung cancer.     

A review on the role of antioxidants in the management of diabetes and its complications.

Diabetes is a prevalent systemic disease affecting a significant proportion of the population worldwide. The effects of diabetes are devastating and well documented. There is increasing evidence that in certain pathologic states, especially chronic diseases, the increased production and/or ineffective scavenging of reactive oxygen species (ROS) may play a critical role. High reactivity of ROS determines chemical changes in virtually all cellular components, leading to lipid peroxidation. Production of ROS and disturbed capacity of antioxidant defense in diabetic subjects have been reported. It has been suggested that enhanced production of free radicals and oxidative stress is central event to the development of diabetic complications. This suggestion has been supported by demonstration of increased levels of indicators of oxidative stress in diabetic individuals suffering from complications. Therefore, it seems reasonable that antioxidants can play an important role in the improvement of diabetes. There are many reports on effects of antioxidants in the management of diabetes. In this paper, after complete bibliography and criticizing all relevant articles, the relationships between diabetes and oxidative stress and use of antioxidants in the management of diabetes and its complications have been well reviewed. This review well indicates that oxidative stress is involved in the pathogenesis of diabetes and its complications. Use of antioxidants reduces oxidative stress and alleviates diabetic complications.